β-sulfonyl hydroxamic acids

ABSTRACT

The present invention provides a compound of formula I ##STR1## or pharmaceutical acceptable salts thereof wherein R 1  is C 4-12  alkyl, C 4-12  alkenyl, C 4-12  alkynyl, --(CH 2 ) h  -C 3-8  cycloalkyl, --(CH 2 ) h  -aryl, or --(CH 2 ) h  -het; R 2  is C 1-12  alkyl, C 2-12  alkenyl, C 2-12  alkynyl, --(CH 2 ) h  -C 3-8  cycloalkyl, --(CH 2 ) h  -C 3-8  cycloalkenyl, --(CH 2 ) h  -aryl, --(CH 2 ) h  -het, --(CH 2 ) h  -Q, --(CH 2 ) i  -X-R 4 , or --(CH 2 ) i  CHR 5  R 6 . The compounds are inhibitors of matrix metalloproteinases involved in tissue degradation.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of the following provisionalapplication: U.S. Ser. No. 60/026,848, filed Sep. 27, 1996, under 35 USC119(e)(i).

FIELD OF THE INVENTION

The present invention relates to novel β-sulfonyl hydroxamic acids, topharmaceutical compositions containing them, and to the method of usingthem. The compounds of the invention are inhibitors of matrixmetalloproteinases involved in tissue degradation.

BACKGROUND OF THE INVENTION

Loss of connective tissue integrity occurs in many disease processes,including osteoarthritis, rheumatoid arthritis, septic arthritis,osteopenias such as osteoporosis, tumor metastasis (invasion andgrowth), periodontitis, gingivitis, corneal ulceration, dermalulceration, gastric ulceration, inflammation, asthma and other diseasesrelated to connective tissue degradation. Although there is a highincidence of these diseases in the developed world, there is notreatment that prevents the tissue damage that occurs. Considerablelines of scientific evidence indicate that uncontrolled connectivematrix metalloproteinase (MMPs) activity is responsible for the damage,and as a consequence the inhibition of these enzymes has become thetarget for therapeutic intervention (see Matrisian, L. M., Bases, Vol.14, pp 445-463 (1992); Emonard, H. et al., Cellular and molecularBiology, Vol. 36, pp 131-153 (1990); Docherty, A. J. P. et al., Annalsof the Rheumatic, Vol. 49, pp 469-479 (1990)).

Hydroxamic acid derivatives are a class of known therapeutically activeMMPs inhibitors and there are numerous references in the art disclosinga variety of hydroxamic acid derivatives. For example, European PatentPublication 0,606,046 A1 discloses arylsulfonamido-substitutedhydroxamic acids useful as matrix metalloproteinase inhibitors.International Publication Nos. WO 95/35275 and WO 95/35276 disclosesulfonamide hydroxamic acid and carboxylic acid derivatives useful asmatrix metalloproteinases inhibitors. All these references relate tosulfonamide hydroxamic acids. The compounds of this invention are noveland distinct from all other sulfonamide hydroxamic acids in that theusual nitrogen atom is replaced by a carbon atom. The invention providessulfonyl hydroxamic acid derivatives.

The compounds of the present invention inhibit various enzymes from thematrix metalloproteinase family, predominantly stromelysin andgelatinase, and hence are useful for the treatment of matrix metalloendoproteinase diseases such as osteoporosis, tumor metastasis (invasionand growth), periodontitis, gingivitis, corneal ulceration, dermalulceration, gastric ulceration, inflammation, asthma, and other diseasesrelated to connective tissue degradation.

INFORMATION DISCLOSURE

The following references disclose sulfonyl hydroxamic acid derivatives.

International Publication No. WO 95/09841 discloses hydroxamic acidcompounds useful as inhibitors TNF and matrix metalloproteinases.

International Publication No. WO 93/20047 discloses hydroxamic acidcompounds useful as inhibitors of tumour necrosis factor production andof matrix metalloproteinases.

International Publication No. WO 90/05719 discloses hydroxamic acidcompounds useful in the management of diseases involving tissuedegradation and/or the promotion of wound healing.

The hydroxamic acid compounds in the above identified references have anobligatory peptide backbone. The compounds of the present invention aredistinct from the above noted references in that they do not have apeptide backbone.

The European Patent Application EP 0780 386 A1 discloses matrixmetalloproteinases inhibitors useful in the treatment of mammals havingdisease states alleviated by the inhibition of such matrixmetalloproteinases.

International Publication No. WO 97/24117 discloses substituted aryl,heteroaryl, arylmethyl or heteroarylmethyl hydroxamic acid compoundsespecially useful for inhibiting the production or physiological effectsof TNF in the treatment of a patient suffering from a disease stateassociated with a physiologically detrimental excess of tumor necrosisfactor (TNF).

SUMMARY OF THE INVENTION

The present invention provides novel compounds of formula I ##STR2## orpharmaceutical acceptable salts thereof wherein: R₁ is

a) C₄₋₁₂ alkyl,

b) C₄₋₁₂ alkenyl,

c) C₄₋₁₂ alkynyl,

d) --(CH₂)_(h) -C₃₋₈ cycloalkyl,

e) --(CH₂)_(h) -aryl,

f) --(CH₂)_(h) -aryl substituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, halo,--NO₂, --CF₃, --CN, or --N(C₁₋₄ alkyl)₂,

g) --(CH₂)_(h) -het, or

h) --(CH₂)_(h) -het substituted with C₁₋₄ alkyl, or halo;

R₂ is

a) C₁₋₁₂ alkyl,

b) C₁₋₁₂ alkyl substituted with one to three halo, --CN, --NO₂, --CF₃,--N(R₃)₂, --SR₃, or OH,

c) C₂₋₁₂ alkenyl,

d) C₂₋₁₂ alkenyl substituted with one to three halo, --CN, --NO₂, or--CF₃,

e) C₂₋₁₂ alkynyl,

f) C₂₋₁₂ alkynyl substituted with one to three halo, --CN, --NO₂, or--CF₃,

g) --(CH₂)_(h) -C₃₋₈ cycloalkyl,

h) --(CH₂)_(h) -C₃₋₈ cycloalkyl substituted with one to three C₁₋₄alkyl, C₁₋₄ alkoxy, or halo,

i) --(CH₂)_(h) -C₃₋₈ cycloalkenyl,

j) --(CH₂)_(h) -C₃₋₈ cycloalkenyl substituted with one to three C₁₋₄alkyl, C₁₋₄ alkoxy, or halo,

k) --(CH₂)_(h) -aryl,

l) --(CH₂)_(h) -aryl substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy, --CF₃ --OH, --NO₂, --CN, --N(R₃)₂, --SR₃,--SO₂ (C₁₋₄ alkoxy),--C(═O)R₃, or --NC(═O)R₃,

m) --(CH₂)_(h) -aryl substituted with one to five halo,

n) --(CH₂)_(h) -het,

o) --(CH₂)_(h) -het substituted with one to two C₁₋₄ alkyl, or halo,

p) --(CH₂)_(h) -Q,

q) --(CH₂)_(h) -Q substituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy,halo, or phenyl,

r) --(CH₂)_(i) -X-R₄, optionally the (CH₂)_(i) - chain can besubstituted with C₁₋₄ alkyl or phenyl, which in turn can be substitutedwith one to three halo or C₁₋₄ alkyl, or

s) --(CH₂)_(i) CHR₅ R₆ ;

R₃ is

a) H,

b) C₁₋₄ alkyl,

c) --(CH₂)_(h) -phenyl, or

d) --(CH₂)_(h) -phenyl substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy, or halo;

X is

a) --O--,

b) --S(═O)_(j) -,

c) --NR₇ -,

d) --S(═O)₂ NR₈ -, or

e) --C(═O)--;

R₄ is

a) H,

b) C₁₋₄ alkyl,

c) --(CH₂)_(h) -phenyl,

d) --(CH₂)_(h) -phenyl substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy, halo, --NO₂, or --CN, or

e) --(CH₂)_(h) -het;

R₅ is

a) C₁₋₄ alkyl, or

b) --C(═O)R₃ ;

R₆ is

a) --C(═O)R₃, or

b) --(CH₂)_(h) C(═O)R₃ ;

R₇ is

a) H,

b) C₁₋₄ alkyl,

c) --(CH₂)_(h) -phenyl,

d) --(CH₂)_(h) -phenyl substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy, or halo,

e) --C(═O)--R₃,

f) --S(═O)₂ R₃, or

g) --C(═O)OR₃ ;

R₈ is

a) C₁₋₄ alkyl,

b) --(CH₂)_(h) -phenyl, or

c) --(CH₂)_(h) -phenyl substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy, or halo;

aryl is monocarbocyclic, or bicarbocyclic aromatic moiety;

het is 5- to 10-membered unsaturated heterocyclic moiety having one tothree atoms selected from the group consisting of oxygen, nitrogen, andsulfur;

Q is 5- to 10-membered saturated heterocyclic moiety having one to twoatoms selected from the group consisting of oxygen, nitrogen, andsulfur;

h is 0, 1, 2, 3, 4, 5, or 6; i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;and j is 0, 1, or 2.

The compounds of the present invention inhibit various enzymes from thematrix metalloproteinase family, predominantly stromelysin andgelatinase, and hence are useful for the treatment of matrix metalloendoproteinase diseases

DETAILED DESCRIPTION OF THE INVENTION

For the purpose of the present invention, the carbon content of varioushydrocarbon containing moieties is indicated by a prefix designating theminimum and maximum number of carbon atoms in the moiety, i.e., theprefix C_(i-j) defines the number of carbon atoms present from theinteger "i" to the integer "j", inclusive. Thus, C₁₋₄ alkyl refers toalkyl of one to four carbon atoms, inclusive, or methyl, ethyl, propyl,butyl and isomeric forms thereof.

The terms "C₁₋₄ alkyl", "C₄₋₈ alkyl", "C₁₋₁₂ alkyl", and "C₁₋₁₈ alkyl"refer to an alkyl group having one to four, four to eight, one totwelve, or one to eighteen carbon atoms respectively such as; forexample, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl and their isomericforms thereof, preferably an alkyl group of R₁ having four to eightcarbon atoms, and an alkyl group of R₂ having one to eight carbon atoms.

The terms "C₂₋₁₂ alkenyl" and "C₄₋₈ alkenyl" refer to at least onedouble bond alkenyl group having two to twelve carbon atoms respectivelysuch as; for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl,heptenyl, heptdienyl, octenyl, octadienyl, octatrienyl, nonenyl,undecenyl, dodecenyl, and their isomeric forms thereof, preferably analkenyl group of R₁ having four to eight carbon atoms, and an alkenylgroup of R₂ having two to eight carbon atoms.

The term "C₂₋₁₂ alkynyl" refers to at least one triple bond alkynylgroup having two to twelve carbon atoms such as; for example, ethynyl,propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, octadiynyl,octatriynyl, nonynyl, nonediynyl, and their isomeric forms thereof,preferably an alkynyl group of R₁ having four to eight carbon atoms, andan alkenyl group of R₂ having two to eight carbon atoms.

The term "C₃₋₈ cycloalkyl" refers to a cycloalkyl having three to eightcarbon atoms such as; for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, and their isomeric forms thereof,preferably an cycloalkyl group having three to six carbon atoms.

The term "C₃₋₈ cycloalkenyl" refers to a cycloalkenyl having three toeight carbon atoms such as; for example, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and theirisomeric forms thereof, preferably an cycloalkyl group having five tosix carbon atoms.

The terms "C₁₋₄ alkoxy", "C₁₋₆ alkoxy", and "C₁₋₈ alkoxy" refer to analkyl group having one to four, one to six, or one to eight carbon atomsrespectively attached to an oxygen atom of hydroxyl group such as; forexample, methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy,heptyloxy, or octyloxy and their isomeric forms thereof.

The term "aryl" refers to monocarbocyclic or bicarbocyclic aromaticmoiety such as; for example phenyl, naphthyl, biphenyl. Each of thesemoieties may be substituted as appropriate. Aryl is preferably phenyl orphenyl substituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro, chloro, bromo,--NO₂, --CF₃, --N(C₁₋₄ alkyl)₂, --C(═O)R₃, or --NC(═O)R₃.

The term "het" refers to a 5- to 10-membered unsaturated heterocyclicmoiety having one or more atoms selected from the group consisting ofoxygen, nitrogen, and sulfur such as; for example, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl,4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl,3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl,2-quinoxalinyl, 1-phthalazinyl, 2-imidazolyl, 4-imidazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl,5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl,4-thiazolyl, 5-thiazolyl, 3-isothiazole, 4-isothiazole, 5-isothiazole,2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl,2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, benzoisothiazole,benzoisoxazole, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl,3-pyrrolyl, 3-isopyrrolyl, 4-isopyrrolyl, 5-isopyrrolyl, 1-indolyl,1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl and5-isothiazolyl, preferably pyridyl, quionlinyl, pyrrolyl, thienyl,thiazolyl, or indolyl. Each of these moieties may be substituted withone to two C₁₋₄ alkyl, --NO₂, fluoro, chloro, or bromo as appropriate.

The term "Q" refers to a 5- to 10-membered saturated heterocyclic moietyhaving one to two atoms selected from the group consisting of oxygen,nitrogen, and sulfur such as; for example, piperidinyl, 2-, 3-, or4-piperidinyl, 1,4!piperazinyl, morpholinyl, 2- or 3-morpholinyl,thiomorpholinyl, dioxolanyl, imidazolidinyl, 1,3!oxathiolanyl,1,3!oxazolidinyl, pyrrolidinyl, butyrolactonyl, butyrolactamyl,succinimidyl, glutarimidyl, valerolactamyl, 2,5-dioxo- 1,4!-piperazinyl,pyrazolidinyl, 3-oxopyrazolidinyl, 2-oxo-imidazolidinyl,2,4-dioxo-imidazolidinyl, 2-oxo- 1,3!-oxazolidinyl, 2,5-dioxo-1,3!-oxazolidinyl, isoxazolidinyl, 3-oxo-isoxazolidinyl,1,3!-thiazolidinyl, 2- or 4-oxo- 1,3!-thiazolidinyl, preferablybutyrolactamyl, succinimidyl, glutarimidyl, valerolactamyl, 2,5-dioxo-1,4!-piperazinyl, 3-oxopyrazolidinyl, 2-oxo-imidazolidinyl,2,4-dioxo-imidazolidinyl, 2-oxo- 1,3!-oxazolidinyl, 2,5-dioxo-1,3!-oxazolidinyl, 3-oxo-isoxazolidinyl, 2- or 4-oxo-1,3!-thiazolidinyl.

The term halo refers to fluoro, chloro, bromo, or iodo, preferablyfluoro, chloro, or bromo.

The compounds of the present invention can be converted to their salts,where appropriate, according to conventional methods.

The term "pharmaceutically acceptable salts" refers to acid additionsalts useful for administering the compounds of this invention andinclude hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate,acetate, propionate, lactate, mesylate, maleate, malate, succinate,tartrate, citric acid, 2-hydroxyethyl sulfonate, fumarate and the like.These salts may be in hydrated form. Some of the compounds of thisinvention may form metal salts such as sodium, potassium, calcium andmagnesium salts and these are embraced by the term "pharmaceuticallyacceptable salts".

The compounds of formula I of this invention contain a chiral center atthe α-position of hydroxamic acids, as such there exist two enantiomersor a racemic mixture of both. This invention relates to both theenantiomers, as well as mixtures containing both the isomers. Inaddition, depending on the substituents, additional chiral centers andother isomeric forms may be present in any of the R₂ groups, and thisinvention embraces all possible stereoisomers and geometric forms inthis group.

R₁ is preferably n-butyl, isobutyl, 1-methylpropyl, tert-butyl,n-pentyl, 3-methybutyl, n-hexyl, n-heptyl, n-octyl, phenyl,4-methylphenyl, 4-ethylphenyl, 4-tert-butylphenyl, 4-isopropylphenyl,4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl,4-methoxyphenyl, 4-ethoxyphenyl, 4-n-butyloxyphenyl, benzyl,4-phenylbenzyl, 2-, 3-, or 4-fluorobenzyl, 2-, 3-, 4-chlorobenzyl, 2-,3-, 4-bromobenzyl, and 4-ethoxybenzyl. More preferably R₁ is n-butyl,n-pentyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl,4-ethylphenyl, 4-isopropylphenyl, 4-chlorophenyl, 4-bromophenyl,4-fluorophenyl, 4-methoxyphenyl, 4-butoxyphenyl, benzyl, 4-fluorobenzyl,4-chlorobenzyl, 4-bromobenzyl, and 4-ethoxybenzyl.

R₂ is preferably methyl, 1-cyano-1-phenyl methyl, 2-cyano ethyl,2-phenylethyl, 2-bromo-2-phenylethyl, 2-bromoethyl, propyl, isopropyl,3-chloropropyl, 3-bromopropyl, n-butyl, isobutyl, 3-methylbutyl,1-methylpropyl, tert-butyl, n-pentyl, 3-methybutyl, n-hexyl, n-heptyl,n-octyl, n-hexadecyl, n-octadecyl, 2-propenyl, 2-propynyl, 3-butenyl,4-pentenyl, 3-butenynyl, 4-pentenynyl, cyclopentyl, cyclohexyl,cyclohexylmethyl, 2-cyclohexylethyl, 4-cyclohexylbutyl,dimethylaminoethyl, dimethylaminopropyl, diethylaminopropyl,phenylaminomethyl, phenyl, 4-methylphenyl, 4-chlorophenyl,4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl,4-methoxyphenyl, 4-nitrophenyl, 4-ethoxyphenyl, benzyl, 4-methylbenzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl,4-bromobenzyl, and 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,4-ethoxybenzyl, 4-nitrobenzyl, methylcarbonyl, 1-methylcarbonyl methyl,2-phenylcarbonyl ethyl, isopropylcarbonyl, methoxycarbonyl,ethoxycarbonyl, 1,1-ethoxycarbonyl methyl, 2,2-ethoxycarbonyl ethyl,1,2-ethoxycarbonyl ethyl, 2-methoxycarbonyl propyl, 3-methoxycarbonylpropyl, 1-ethoxycarbonyl methyl, 1-ethoxycarbonyl ethyl, phenylcarbonyl,phenylcarbonyl methyl, pyridylcarbonyl methyl, pyridylmethyl,pyridylethyl, quionlinylmethyl, pyrrolyl methyl, indolyl methyl,thienyl, thiazolyl, thienylmethyl, thienylethyl, piperdinyl methyl,piperazinyl methyl, morpholino methyl, morpholino ethyl, morpholinopropyl, thiomorpholino methyl, thiomorpholino propyl,4-methoxybenzenesulfonyl methyl, 3-(4-methoxybenzenesulfonyl)aminopropyl, 3-(4-methoxybenzenesulfonyl)propyl, 3-hydroxy, amino, 3-phenoxypropyl, 2-phenyl ethyloxy, (4-butoxybenzenesulfonyl) methyl, methyl-3-(1,5,5-trimethylhydantoin), methyl-3-( 1-butyl-5,5-dimethylhydantoin),(4-methoxybenzenesulfonyl)methyl, (4-chlorobenzenesulfonyl)-methyl,(4-bromobenzenesulfonyl)methyl, (n-butylsulfonyl)methyl,(n-octylsulfonyl)-methyl, 3-(4-methoxybenzenesulfonyl)propyl,(4-methylbenzenesulfonyl)methyl, (benzenesulfonyl)methyl,methyl-3-(1-methylhydantoin), methyl-3-(1-butylhydantoin) andmethyl-3-(5,5-dimethylhydantoin). More preferably R₂ is(4-methoxybenzenesulfonyl)methyl, (4-chlorobenzenesulfonyl)-methyl,(4-bromobenzenesulfonyl)methyl, (n-butylsulfonyl)methyl,(n-octylsulfonyl)methyl, 3-(4-methoxybenzenesulfonyl)propyl,(4-methylbenzenesulfonyl)methyl, (benzenesulfonyl)methyl,methyl-3-(1-methylhydantoin), methyl-3-(1-butylhydantoin) andmethyl-3-(5,5-dimethylhydantoin).

Particularly preferred compounds of this invention are as follows:

(1) N-hydroxy 2- (4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionamide,

(2) N-hydroxy 2- (benzenesulfonyl)methyl!-3-phenyl-propionamide,

(3) N-hydroxy 2- (benzenesulfonyl)methyl!-propionamide,

(4) N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide,

(5) N-hydroxy-2-(4-chlorobenzenesulfonyl)methyl!-3-(4-chlorobenzenesulfonyl)-propionamide,

(6) N-hydroxy-2-(4-bromobenzenesulfonyl)methyl!-3-(4-bromobenzenesulfonyl)-propionamide,

(7) N-hydroxy-2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionamide,

(8) N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(n-octylsulfonyl)-propionamide,

(9) N-hydroxy-2-(4-methylbenzenesulfonyl)methyl!-3-(4-methylbenzenesulfonyl)-propionamide,

(10) N-hydroxy-2-(benzenesulfonyl)methyl!-3-(benzenesulfonyl)-propionamide,

(11) N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanamide,

(12) N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide,

(13) N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,

(14) N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,

(15) N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,

(16) N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzene-sulfonyl)-propionamide,

(17) (+)-N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide,

(18) (-)-N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide,

(19) (+)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide

(20) (-)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide

(21) (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,

(22) (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,

(23) (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,

(24) (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,

(25) (+)-N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,or

(26) (-)-N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.

The compounds of this invention can be prepared in accordance to theprocess discussed below.

In Scheme I, R₁ and R₂ are the groups as defined previously. Substitutedmalonate esters 2 are either obtained commercially, or can be readilyprepared from structure 1 by methods well known to those skilled in theart. For example, reaction of an enolate of structure 1, generated by anappropriate base in an appropriate solvent, with an alkylating agent R₂-I (I is bromo, chloro, tosylate, mesylate, epoxides, etc.) provides thedesired substituted malonate esters 2. See: Organic Synthesis, Vol. 1 p250 (1954); Organic Synthesis, Vol. 3, p 495 (1955). Compound 2 ishydrolyzed to mono-acid compound 3 by reaction with one equivalent of anappropriate base such as alkali hydroxide in an appropriate solvent at atemperature ranging from 0° C. to 30° C. In the presence of formaldehydeand piperidine in an appropriate solvent such as pyridine, ethanol,dioxane at refluxing temperatures, compound 3 is converted to acrylicesters 4. In many cases, acrylic esters 4 are commercially available. Athiol (H-SR₁) is add to the acrylic ester 4 at room temperature toafford sulfide esters 5 in the presence of either a catalytic amount ofalkoxide in alcoholic solvent or a tertiary amine base in chloroform.The resultant sulfides 5 are readily oxidized to sulfones 6 by anoxidizing agent such as meta-chloroperbenzoic acid (MCPBA) in anappropriate solvent such as methylene chloride, or using hydrogenperoxide in acetic acid as a solvent. The esters can be hydrolyzed byprocedures well known in the art such as using 6N HCl and refluxing for10 to 20 hours or using iodotrimethylsilane in chloroform to afford freeacids 7. Coupling of acids 7 with hydroxylamine hydrochlorides to formhydroxamates 9 may be achieved by several routes well known to thoseskilled in the art. For example, acids 7 can be activated bychloroethylformate in dry THF or a similar compatible solvent, or by acarbodiimide condensing agent such as EDC, with or without HOBT, in DMFand methylene chloride. A tertiary amine is required in both situations.The subsequent reaction of activated 7 with hydroxylamine provides thedesired hydroxamic acid derivatives. Alternatively, acids 7 may becondensed, using the same reagents as described above, withbenzyl-protected hydroxylamine hydrochloride, to produce the protectedhydroxamates 8. Compounds 8 are often easier to purify, and may readilybe hydrogenolytically cleaved to the free hydroxamates 9 by a palladiumcatalyst in alcoholic solvents. Other protected hydrocylamines such astert-butyl hydroxylamine may also be used, and the free hydroxamate canbe obtained by treating it with trifluoroacetic acid.

A second method of preparing the compounds of the invention is toutilize commercially available acrylic acids 10 as shown in Scheme II.Treatment of acrylic acids with thiols affords compounds 11. Thereaction may be accomplished in refluxing an appropriate solvent such asdioxane with piperidine as a catalyst. See: Annelen, Vol. 564, pp 73-78(1949). A variation of this method is shown in Scheme III in whichax-bromomethyl acrylic acids 12 are reacted with two moles of thiols toafford bis-sulfides 13. Oxidation of the resulting sulfides withmeta-chloroperbenzoic acid or with excess hydrogen peroxide providescompound 7 in Scheme II and compound 14 in Scheme III, respectively. Theremaining synthetic steps which lead to products 9 and 15 are similar tothe procedures outlined in Scheme I.

Schemes IV, V and VI depict methods especially adapted to thepreparation of the compounds of formula I wherein the R₂ group containsheteroatoms. In Scheme IV, substituent R₄ is defined as previously.Group I in structure 16 is bromo, chloro, tosylate, mesylate, orepoxides, and may be replaced by an agent R₄ -X-H according toprocedures well known in the art (X may be O, NR₇, S and etc.). Theremaining synthetic steps which lead to compound 18 are similar to theprocedures outline in Scheme I.

In Scheme V a suitably protected cysteine (P in structure 19 is aprotecting group) can be converted to the corresponding thiol 20. Afterremoving the protecting group, a R₇ group (as defined previously) can beintroduced into the nitrogen atom as shown in structure 23. Theprocedure outlined in Scheme V is discussed in further detail inSynthesis Communication, Vol. 16, No. 5, p. 565 (1986). This method canbe carried out for both the racemate or a single enantiomer. Followingthe general procedures as described above but starting withenantiomerically enriched isomers, the desired single enantiomer, eitherR or S can be obtained.

In Scheme VI, structure 12 is first reacted with one equivalent of thiolor sulfinate in a suitable solvent such as toluene in the absence orpresence of a suitable base such as sodium bicarbonate or triethylamine, at ambient temperature or reflux, to afford 25 or 26,respectively. Conversion of 25 to 26 is accomplished with an oxidantsuch as meta-chloroperbenzoic acid, in a suitable solvent such asmethylene chloride at 0° C. Intermediate 26 is reacted with the anion orconjugate acid of W (wherein W is a group attached via a heteroatom suchas oxygen, nitrogen or sulfur) in a solvent such as toluene ordimethylformamide, in the absence or presence of a basic catalyst suchas sodium bicarbonate or triethyl amine, preferably at reflux to provideintermediate 7, in which the R₂ group may be --CH₂ XR₄, --CH₂ -het, or--CH₂ -Q. The remaining synthetic steps which lead to final hydroxamicproducts 9 are similar to the procedures outlined in Scheme I.

In addition to Schemes IV, V and VI, the compounds of formula I whereinthe R₂ group contains heteroatoms may also be prepared according toScheme II by using structure 12. In this method, α-bromomethyl acrylicacid 12 is reacted with one equivalent of anion or conjugate acid of Wto provide acrylic acids 10, in which the R₂ group may be --CH₂ -W(wherein W is as defined above). The remaining synthetic steps whichlead to final hydroxamic products 9 are similar to the proceduresoutlined in Scheme II. When W is a thiol or thiolate, the sulfurcontained in R₂ may be oxidized to a sulfoxide or sulfone, give rise to,for example, unsymmetrical bis-sulfonyl hydroxamates.

The chemistry in Schemes I, II, IV and VI proceeds through achiral orracemic intermediates and pure enantiomers of the final products may beobtained by resolution of intermediates 5-9 or 11 by chiralchromatography or classical derivatization methods such as chiral saltformation of intermediate 7.

The pharmaceutical compositions of this invention may be prepared bycombining the compounds of formula I of this invention with a solid orliquid pharmaceutically acceptable carrier, and optionally, withpharmaceutically acceptable adjuvants and excipients employing standardand conventional techniques. Solid form compositions include powders,tablets, dispersible granules, capsules and suppositories. A solidcarrier can be at least one substance which may also function as adiluent, flavoring agent, solubilizer, lubricant, suspending agent,binder, tablet disintegrating agent, and encapsulating agent. Inertsolid carriers include magnesium carbonate, magnesium stearate, talc,sugar, lactose, pectin, dextrin, starch, gelatin, cellulosic materials,low melting wax, cocoa butter, and the like. Liquid form compositionsinclude solutions, suspensions and emulsions. For example, there may beprovided solutions of the compounds of this invention dissolved inwater, water-propylene glycol, and water-polyethylene glycol systems,optionally containing conventional coloring agents, flavoring agents,stabilizers and thickening agents.

The pharmaceutical composition is provided by employing conventionaltechniques. Preferably the composition is in unit dosage form containingan effective amount of the active component, that is, the compounds offormula I according to this invention.

The quantity of active component, that is the compounds of formula Iaccording to this invention, in the pharmaceutical composition and unitdosage form thereof may be varied or adjusted widely depending upon theparticular application method, the potency of the particular compoundand the desired concentration. Generally, the quantity of activecomponent will range between 0.5% to 90% by weight of the composition.

In therapeutic use for treating a patient, suffering from or susceptibleto diseases involving connective tissue degradation, or inhibitingvarious enzymes from the matrix metalloproteinase family, includingcollagenase, stromelysin, and gelatinase, the compounds orpharmaceutical compositions thereof will be administered orally,parenterally and/or topically at a dosage to obtain and maintain aconcentration, that is, an amount, or blood-level of active component inthe patient undergoing treatment which will be effective to inhibit suchenzymes. Generally, an effective amount of the active compound will bein the range of about 0.1 to about 100 mg/kg. It is to be understoodthat the dosages may vary depending upon the requirements of thepatient, the severity of connective tissue degradation being treated,and the particular compounds being used. Also, it is to be understoodthat the initial dosage administered may be increased beyond the aboveupper level in order to rapidly achieve the desired blood-level or theinitial dosage may be smaller than the optimum and the daily dosage maybe progressively increased during the course of treatment depending onthe particular situation. If desired, the daily dose may also be dividedinto multiple doses for administration, e.g., two to four times per day.

The compounds of the present invention inhibit various enzymes from thematrix metalloproteinase family, predominantly stromelysin andgelatinase, and hence are useful for the treatment of matrix metalloendoproteinase diseases such as osteoarthritis, rheumatoid arthritis,septic arthritis, osteopenias such as osteoporosis, tumor metastasis(invasion and growth), periodontitis, gingivitis, corneal ulceration,dermal ulceration, gastric ulceration, and other diseases related toconnective tissue degradation. Such diseases and conditions are wellknown and readily diagnosed by physician of ordinary skill.

Pharmaceutical compositions for parenteral administration will generallycontain a pharmaceutically acceptable amount of the compounds accordingto formula I as a soluble salt (acid addition salt or base salt)dissolved in a pharmaceutically acceptable liquid carrier such as; forexample, water-for-injection and a suitably buffered isotonic solutionhaving a pH of about 3.5-6. Suitable buffering agents include; forexample, trisodium orthophosphate, sodium bicarbonate, sodium citrate,N-methylglucamine, L(+)-lysine and L(+)-arginine, to name a few. Thecompounds according to formula I generally will be dissolved in thecarrier in an amount sufficient to provide a pharmaceutically acceptableinjectable concentration in the range of about 1 mg/ml to about 400mg/ml. The resulting liquid pharmaceutical composition will beadministered so as to obtain the above-mentioned inhibitory effectiveamount of dosage. The compounds of formula I according to this inventionare advantageously administered orally in solid and liquid dosage forms.

The compounds and their preparations of the present invention will bebetter understood in connection with the following examples, which areintended as an illustration of and not a limitation upon the scope ofthe invention.

EXAMPLE 1

Preparation of N-hydroxy 2- (4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionamide. ##STR3## Step 1 Preparation ofbenzylmalonic acid monoethyl ester.

Benzylmalonic acid diethyl ester (10 g, 40 mmol) in 25 mL of ethanol iscooled to 0° C. Potassium hydroxide (2.5 g, 40 mmol) dissolved in 25 mLof ethanol is added dropwise over 50 minutes. The cooling bath isremoved and the mixture is stirred for one additional hour. The volumeof solvent is reduced by evaporation in vacuo, and the residual solutionis poured into aqueous sodium bicarbonate solution and extracted twicewith ethyl acetate. The aqueous phase is acidified with aqueous 10% HCland extracted twice with ethyl acetate. The organic phase is dried witha brine extraction, filtered from anhydrous sodium sulfate, andconcentrated in vacuo, yielding 8.08 g of the title compound as acolorless oil.

Step 2 Preparation of 2-benzyl-2-propenoic acid ethyl ester.

Benzylmalonic acid monoethyl ester (8.0 g, 36 mmol), 7 mL of pyridine,0.36 mL (3.6 mmol) of piperidine, and 1.06 g (35 mmol) ofparaformaldehyde is refluxed under nitrogen for 1.5 hours in an oil bathmaintained at 130° C. After cooling for 0.5 hours the mixture ispartitioned between 100 mL of water and 100 mL of hexane. The aqueousphase is re-extracted with 50 mL of hexane. The organic phase is washedwith aqueous 10% HCl, water, 1M sodium bicarbonate, and brine. It isdried over anhydrous sodium sulfate and concentrated in vacuo, yielding5.8 g of the title compound as a colorless oil.

Step 3 Preparation of 2-(4-methoxybenzenethio)methyl!-3-phenyl-propenoic acid ethyl ester.

4-Methoxybenzenethiol (0.6 mL, 4.7 mmol) in 1 mL of ethanol is cooled inan ice bath with stirring. Ethanolic sodium ethoxide solution 0.13 ml(0.34 mmol) is added. After 15 minutes 1.0 g (5.3 mmol) of2-benzyl-2-propenoic acid ethyl ester in 1 mL of ethanol is addeddropwise over about 2 minutes. The ice bath is removed and the reactionmixture is allowed to stir for 17 hours. The mixture is evaporated invacuo and partitioned between ethyl acetate and aqueous 5% HCl. Theorganic phase is concentrated and chromatographed over silica gel,eluting with hexane:acetone (98:2), to afford 1.04 g of the titlecompound as a colorless oil.

Step 4 Preparation of 2-(4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionic acid ethyl ester.

To a solution of 2- (4-methoxybenzenethio)methyl!-3-phenyl-propionicacid ethyl ester (1.51 g, 4.6 mmol) in 50 mL of methylene chloride,cooled in an ice bath, is added 2.17 g (10 mmol) of solid MCPBA portionwise over 5 minutes. The cooling bath is removed, and the mixture isstirred at room temperature overnight. The suspension is filtered andthe solids washed with methylene chloride. The organic solution isextracted with three portions of 1M sodium bicarbonate, dried byextraction with brine, filtered from anhydrous sodium sulfate, andconcentrated. Chromatography on silica gel, eluting with methylenechloride:acetone (99:1), afforded 1.31 g of the title compound as acolorless oil.

Step 5 Preparation of 2-(4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionic acid.

A mixture of 0.56 g (1.5 mmol) of 2-(4-methoxybenzenesulfonyl)methyl!-3-phenyl-propanoic acid ethyl esterand 8 ml of 6N HCl is heated at 115° C. for 17 hours. The mixture istransferred to 100 ml of ice-water and extracted with two portions ofethyl acetate. The organic phase is extracted with three 50 mL portionsof aqueous 5% sodium bicarbonate. The bicarbonate solution is pouredover ice and acidified with concentrated HCl. The acidified aqueousmixture is extracted with three 50 mL portions of ethyl acetate and thecombined organic extracts are concentrated in vacuo to yield 0.45 g ofthe title compound as a white solid.

Step 6 Preparation of N-benzyloxy-2-(4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionamide.

A solution of 2- (4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionicacid (1.05 g, 3.14 mmol) and 0.69 mL (6.3 mmol) of NMM in dry THF, undernitrogen, is cooled in an ice bath. Ethyl chloroformate (0.33 mL, 3.5mmol) in 7 mL of THF is added dropwise over 5 minutes. The suspension isstirred at 0° C. for 10 minutes, after which a slurry ofO-benzylhydroxylamine hydrochloride (0.64 g, 4 mmol) and NMM (0.44 mL, 4mmol) in 7 mL of THF is introduced in several portions. The mixture isstirred for 10 minutes and stored at 10° C. overnight. The mixture isallowed to warm to room temperature for 0.5 hours, and is thenpartitioned between ethyl acetate and aqueous 10% HCl. The organic phaseis washed with water, three portions of 1M sodium bicarbonate and brine.It is dried over anhydrous sodium sulfate, concentrated andchromatographed on silica gel, eluting with 40%-50% ethyl acetate inhexanes. This affords 1.26 g of the title compound as a colorless oil.

Step 7 Preparation of N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionamide.

N-benzyloxy-2- (4-methoxybenzenesulfonyl)methyl!-3-phenyl- propionamide(1.25 g, 2.85 mmol) is dissolved in 45 mL of ethanol. To this is added0.36 g of palladium hydroxide on carbon (Pearlman's catalyst), and thesuspension is placed in a shaker under 15 psi of hydrogen for 2.25hours. The catalyst is filtered off, washing with ethanol, and theethanol solution is concentrated in vacuo to afford, after evaporationfrom methylene chloride, 0.875 g of the title compound as a white solid.

¹ H NMR (DMSO) δ 10.6, 8.8, 7.67, 7.17-7.22, 7.03-7.1, 3.85, 3.55, 3.02,2.76-2.79, 2.62; ¹³ C NMR (DMSO) δ 168.7, 164.1, 138.5, 131.3, 130.7,129.7, 129.1, 127.3, 115.4, 56.5, 56.5, 38.3, 37.3; MS (EI) m/z 349,317, 288, 214, 171, 155, 145, 117, 107, 91.

EXAMPLE 2

Preparation of N-hydroxy 2-(benzenesulfonyl)methyl!-3-phenyl-propionamide. ##STR4##

Following the general procedure outlined in EXAMPLE 1 (steps 3 to 7) andmaking non-critical variations but starting with thiophenol in step 3,the title compound is obtained as a white solid.

¹ H NMR (DMSO) δ 10.6, 8.8, 7.73, 7.58, 7.17, 7.02, 3.60, 3.07,2.81-2.7, 2.65-2.60; ¹³ C NMR (DMSO) δ 168.2, 139.4, 138.1, 134.3,129.9, 129.3, 128.8, 128.0, 126.9, 60.2, 55.8, 38.4; IR (mull) cm⁻¹3346, 2925, 1633, 1525, 1450, 1284, 1139; MS (EI) m/z 319, 287, 184,164, 145, 125, 117, 91. Calculated for C₁₆ H₁₇ NO₄ S: C, 60.17; H, 5.36;N, 4.39; S, 10.04; Found: C, 60.04; H, 5.46; N, 4.28; S, 9.88.

EXAMPLE 3

Preparation of N-hydroxy 2- (benzenesulfonyl)methyl!-propionamide.##STR5## Step 1 Preparation of 2- (benzenesulfonyl)methyl!-propionoicacid

To 1 mmol of 2- (benzenethio)methyl!-propionic acid in 10 mL ofmethylene chloride cooled in an ice bath is added 0.5 g (2.3 mmol) ofsolid MCPBA in several portions. The reaction mixture is stirred at roomtemperature for 6 hours, and refrigerated overnight. The suspension isfiltered, and the filtrate is concentrated and chromatographed on silicagel, eluting with 25% ethyl acetate and 0.5% acetic acid in hexanes,followed by 50% ethyl acetate, 0.5% acetic acid, in hexanes. Evaporationof the solvents left 0.225 g of the title compound as a white solid.

Step 2 Preparation of N-hydroxy 2-(benzenesulfonyl)methyl!-propionamide.

Following the general procedure outlined in EXAMPLE 1 (steps 6-7) andmaking non-critical variations but starting with 2-(benzenesulfonyl)methyl!-propionoic acid in step 6, the title compoundis obtained as a white solid.

¹ H NMR (DMSO) δ 10.6, 8.8, 7.87, 7.74, 7.64, 3.53, 3.27, 2.58, 1.05; ¹³C NMR (DMSO) δ 170.0, 139.8, 134.4, 129.9, 128.0, 57.6, 32.3, 19.0; MS(EI) m/z 243, 211, 141, 125, 77.

EXAMPLE 4

Preparation of N-hydroxy-2-(4-methoxybenzene-sulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide##STR6## Step 1 Preparation of2-(4-methoxybenzenethiomethyl)-3-(4-methoxybenzenethio)-propionic acid.

To a stirred mixture of 2-bromomethylacrylic acid (10 g, 60 mmol) in 125mL of toluene at room temperature, is added sodium bicarbonate (15 g,180 mmol) and 4-methoxybenzenethiol (16.5 mL, 140 mmol) and this mixtureis refluxed overnight. The mixture is partitioned between aqueous sodiumbicarbonate and ethyl acetate, the aqueous phase is acidified to pH 2with concentrated hydrochloric acid, and extracted with ethyl acetate.The combined organic extracts are concentrated in vacuo to afford thetitle compound as white solid.

¹ H NMR (DMSO) δ 12.1, 7.25, 6.85, 3.74, 3.05, 2.50; ¹³ C NMR (DMSO) δ174.60, 159.59, 134.05, 125.57, 115.66, 55.93, 55.63, 45.38, 36.93.

Step 2 Preparation of2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionicacid.

A stirred mixture of2-(4-methoxybenzenethiomethyl)-3-(4-methoxybenzenethio)-propionic acid(18.5 g, 5 mmol) in methylene chloride (250 mL) is cooled in a dryice/acetone bath and m-chloroperoxybenzoic acid (MCPBA) (54.5 g, 213mmol) is added in small portions over approximately 30 minutes. Afterstirring at ambient temperature for two days and standing for one daythe mixture is filtered in vacuo over a plug of silica gel 60 (230-400mesh) and the filtrand is eluted with chloroform followed bychloroform/methyl alcohol/acetic acid (89:10:1). The filtrate isconcentrated and triturated with hexane to afford the title compound asa white solid.

m.p. 174°-5° C.; MS (FAB) m/z 430, 429, 239, 171, 109, 107, 103, 89, 61;¹ H NMR (DMSO) δ 7.66, 7.12, 3.86, 3.57, 2.69; ¹³ C NMR (DMSO) δ 171.57,163.97, 130.61, 130.12, 115.13, 56.28, 55.84, 30.04.

Step 3 Preparation ofN-benzyloxy-2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamide.

A mixture of2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionicacid (5.0 g, 12 mmol) in tetrahydrofuran (30 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.3 g, 23mmol), benzylhydroxylamine hydrochloride (2.3 g, 14 mmol), and distilledwater (30 mL) is stirred overnight. The mixture is filtered to yield awhite precipitate which is dissolved in chloroform (200 ml) andfiltered. The filtrate is extracted with brine (100 mL) and the organicphase concentrated in vacuo, to yieldN-benzyloxy-2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamide(2.24 g, 36%). The initial filtrate from the overnight reaction istransferred to ethyl acetate and extracted with 10% hydrochloric acid,water, aqueous sodium bicarbonate, and brine, and concentrated in vacuoto also yield the title compound as a white solid.

m.p. 151° C. (dec.);. ¹ H NMR (DMSO) δ 11.5, 7.70, 7.37, 7.13, 4.69,3.86, 3.50, 2.80; ¹³ C NMR (DMSO) δ 166.68, 164.31, 136.72, 130.96,130.93, 129.65, 129.09, 115.51, 77.56, 56.65, 56.34, 55.72, 34.00.

Step 4 Preparation ofN-hydroxy-2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamide.

A suspension ofN-benzyloxy-2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamide(5.0 g, 9.4 mmol), Pearlman's catalyst (0.9 g), and ethyl alcohol (50mL) is agitated under hydrogen (20 psig) at room temperature overnight.The reaction mixture is filtered through celite and the soluble solidsdissolved with methyl alcohol followed by chloroform/methyl alcohol(9:1). The combined filtrates are concentrated in vacuo to yieldN-hydroxy-2-(4-methoxybenzenesulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamideas a white solid.

m.p. 173.5°-4.5° C.; IR (mull) 3292, 1640, 1597, 1579, 1500, 1320, 1313,1304, 1294, 1282, 1266, 1145, 1089, 1023, 838 cm⁻¹ ; ¹ H NMR (DMSO) δ10.9, 8.9, 7.69, 7.12, 3.87. 3.48, 2.82; ¹³ C NMR (DMSO) δ 166.13,163.93, 130.55, 130.20, 115.15, 55.24, 55.97, 33.47.

EXAMPLE 5

Preparation of N-hydroxy-2-(4-chlorobenzenesulfonyl)methyl!-3-(4-chlorobenzenesulfonyl)-propionamide.##STR7## Step 1 Preparation of2-(4-chlorobenzenesulfonylmethyl)-3-(4-chlorobenzenesulfonyl)-propionicacid.

Following the general procedure in EXAMPLE 4 (steps 1 and 2) and makingnon-critical variations but starting with 4-chlorothiophenol in step 1,the title compound is obtained as a white solid.

m.p. 197° C. (dec.); ¹ H NMR (DMSO) δ 7.77, 7.67, 3.74, 3.54, 2.58; ¹³ CNMR (DMSO) δ 171.24, 139.38, 138.34, 130.26, 129.91, 56.66, 37.59.

Step 2 Preparation of N-hydroxy-2-(4-chlorobenzenesulfonyl)methyl!-3-(4-chlorobenzenesulfonyl)-propionamide.

A mixture of2-(4-chlorobenzenesulfonylmethyl)-3-(4-chlorobenzenesulfonyl)-propionicacid (0.52 g, 1.1 mmol), 1-hydroxybenzotriazole hydrate (0.16 g, 1.2mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.25g, 1.3 mmol), and hydroxylamine hydrochloride (0.083 g, 1.2 mmol) isstirred in an ice bath for 20 minutes and 4-methylmorpholine (0.28 mL,2.5 mmol) in dimethylformamide (10 mL) is added. After stirringovernight at ambient temperature, the mixture is partitioned betweenethyl acetate and aqueous 10% hydrochloric acid. The organic phase isfurther extracted with aqueous acid, aqueous sodium bicarbonate, brine,dried over anhydrous sodium sulfate, concentrated in vacuo. Theconcentrate is chromatographed over silica gel (230-400 mesh) withchloroform/acetone/acetic acid (79/20/1) and the eluate concentrated invacuo, to yield the title compound as a white solid.

m.p. 196°-7.5° C.; MS (FAB) m/z 452, 439, 437, 278, 243, 161, 159, 111;¹ H NMR (DMSO) δ 10.8, 8.93, 7.78, 7.70, 3.59, 2.77; ¹³ C NMR (DMSO) δ165.72, 140.09, 138.08, 130.66, 130.48, 56.01, 33.67.

EXAMPLE 6

Preparation of N-hydroxy-2-(4-bromobenzenesulfonyl)methyl!-3-(4-bromobenzenesulfonyl)-propionamide.##STR8##

Following the general procedure outlined in EXAMPLE 5 (steps 1 and 2)and making non-critical variations but starting with 4-bromothiophenolin step 1, the title compound is obtained as a white solid.

m.p. 187° C. dec.; MS (FAB) m/z 469, 421, 291, 245, 71, 69, 57, 55, 43,41; ¹ H NMR (DMSO) δ 10.9, 8.96, 7.85, 7.70, 3.61, 2.79; ¹³ C NMR (DMSO)δ 165.75, 138.55, 133.42, 130.67, 129.25, 56.01, 33.65.

EXAMPLE 7

Preparation of N-hydroxy-2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionamide. ##STR9## Step1 Preparation of 2- (n-butylthio)methyl!-3-(n-butylthio)-propionic acid,ethyl ester.

A mixture of 4-bromomethylacrylic acid, ethyl ester (1.0 g, 6.0 mmol),n-butylthiol (1.4 mL, 13 mmol), potassium carbonate (1.7 g, 13 mmol) inabsolute ethyl alcohol (25 mL) is stirred at ambient temperatureovernight. The mixture is transferred to ethyl acetate, extracted withaqueous 10% hydrochloric acid, and concentrated in vacuo, to afford thetitle compound as a clear, colorless oil.

¹ H NMR (DMSO) δ 4.07, 2.72, 2.47, 1.47, 1.36, 1.18, 0.86; ¹³ C NMR(DMSO) δ 173.08, 60.65, 46.36, 32.89, 31.61, 21.72, 14.52, 13.90.

Step 2 Preparation of 2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionic acid, ethylester.

After cooling a stirred mixture of 2-(n-butylthio)methyl!-3-(n-butylthio)-propanoic acid, ethyl ester (1.0 g,3.4 mmol) in methylene chloride (30 mL), m-chloroperoxybenzoic acid (3.0g; 14. mmol) is added and the mixture is stirred overnight at ambienttemperature. The mixture is filtered and the filtrate concentrated invacuo to afford 2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propanoic acid, ethyl esteras a clear, colorless oil.

¹ H NMR (DMSO) δ 4.10, 3.51, 3.38, 3.14, 1.63, 1.39, 1.18, 0.85; ¹³ CNMR (DMSO) δ 170.99, 61.79, 52.82, 52.53, 34.20, 23.72, 21.40, 14.22,13.89.

Step 3 Preparation of 2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionic acid.

A mixture of 2- (n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propanoicacid, ethyl ester (1.0 g, 3.0 mmol) in 6N hydrochloric acid (20 mL) isrefluxed overnight. The mixture is transferred to distilled water andextracted with ethyl acetate. The combined organic extracts areconcentrated in vacuo to yield the title compound as a clear, colorlessoil.

¹ H NMR (DMSO) δ 3.50, 3.30, 3.14, 1.62, 1.37, 0.87; ¹³ C NMR (DMSO) δ172.33, 52.88, 52.48, 34.49, 23.75, 21.41, 13.88.

Step 4 Preparation of N-hydroxy-2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionamide.

Following the general procedure outlined in EXAMPLE 4 (steps 3 and 4)and making non-critical variations but starting with 2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionoic acid in step 3,the title compound is obtained as a white solid.

¹ H NMR (DMSO) δ 10.9, 9.0, 3.37, 3.15, 3.09, 1.63, 1.38, 0.88; ¹³ C NMR(DMSO) δ 166.52, 52.93, 52.55, 32.58, 23.73, 21.43, 13.90.

EXAMPLE 8

Preparation of N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(n-octylsulfonyl)-propionamide. ##STR10##

Following the general procedure outlined in EXAMPLE 7 (steps 1 to 4) andmaking non-critical variations but starting with n-octylthiol in step 1,the title compound is obtained as a white solid.

¹ H NMR (DMSO) δ 10.9, 9.05, 3.40, 3.08, 1.61, 1.32, 1.23, 0.84; MS(FAB) m/z 456, 440, 245, 133, 71, 69, 57, 55, 43, 41; ¹³ C NMR (DMSO) δ166.53, 52.92, 52.77, 32.60, 31.64, 28.90, 28.87, 28.14, 22.51, 21.71,14.40.

EXAMPLE 9

Preparation of N-hydroxy-2-(4-methylbenzenesulfonyl)methyl!-3-(4-methylbenzenesulfonyl)-propionamide.##STR11## Step 1 Preparation of 2-(4-methylbenzenesulfonyl)methyl!-3-(4-methylbenzenesulfonyl)propionicacid.

A mixture of 2-bromomethylacrylic acid (2.0 g, 12 mmol),p-toluenesulfinic acid, sodium salt, monohydrate (6.4 g, 27 mmol), andsodium bicarbonate (1.0 g, 12 mmol) in toluene (50 mL) is refluxedovernight. The mixture is transferred to ethyl acetate and extractedwith aqueous 10% hydrochloric acid. The organic phase is concentrated invacuo, and triturated with hexane to yield the title compound as a whitesolid.

¹ H NMR (DMSO) δ 7.66, 7.41, 3.47, 2.82, 2.69; ¹³ C NMR (DMSO) δ 171.46,145.33, 135.72, 130.44, 128.29, 55.47, 36.15, 21.60.

Step 2 Preparation of N-hydroxy-2-(4-methylbenzenesulfonyl)methyl!-3-(4-methylbenzenesulfonyl)-propionamide.

To N-methylpyrrolidinone (20 mL) cooled in an ice bath, is added 2-(4-methylbenzenesulfonyl)methyl!-3-(4-methylbenzenesulfonyl)-propionoicacid (4.4 g, 11 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (4.2 g, 22 mmol), and hydroxylamine hydrochloride (1.5 g,22 mmol). After stirring overnight at ambient temperature, the mixtureis transferred to ethyl acetate and extracted with aqueous 10%hydrochloric acid, distilled water, aqueous sodium bicarbonate, brine,and dried over anhydrous sodium sulfate. The organic phase isconcentrated in vacuo and triturated from hexane to afford the titlecompound as a white solid.

¹ H NMR (DMSO) δ 10.9, 8.9, 7.62, 7.41, 3.47, 2.82, 2.42; ¹³ C NMR(DMSO) δ 165.94, 145.12, 136.19, 130.42, 128.37, 55.87, 33.34, 21.61.

EXAMPLE 10

Preparation of N-hydroxy-2-(benzenesulfonyl)methyl!-3-(benzenesulfonyl)-propionamide. ##STR12##

Following the general procedure outlined in EXAMPLE 9 and makingnon-critical variations but starting with benzenesulfinic acid, sodiumsalt (2.5 g, 15 mmol) in step 1, the title compound is afforded as awhite solid.

Found: C, 50.06; H, 4.56; N, 3.7; S, 16.44; MS (FAB) m/z 386, 385, 384,383, 351, 279, 242, 209, 149, 125; ¹ H NMR (DMSO) δ 10.9, 8.9, 7.75,7.66, 3.53, 2.86; ¹³ C NMR (DMSO) δ 165.83, 139.03, 134.62, 130.02,128.21, 55.77, 33.19.

EXAMPLE 11

Preparation of N-hydroxy-2-(4-methoxybenzenesulfonyl)-methyl!-5-(4-methoxybenzenesulfonyl)-pentanamide.##STR13## Step 1 Preparation of 3-(4-methoxybenzenethio)-propylmalonicacid, diethyl ester.

To a stirred mixture of 3-chloropropylmalonic acid, diethyl ester (2.1g, 8.6 mmol) in dimethylformamide (20 mL) is added 4-methoxybenzenethiol(1.2 mL, 9.5 mmol) in dimethylformamide (20 mL) and sodium bicarbonate(0.72 g, 8.6 mmol). After stirring overnight at room temperature themixture is transferred to ethyl acetate and extracted with aqueous 10%hydrochloric acid, distilled water, aqueous sodium bicarbonate, brine,and concentrated in vacuo. The concentrate is triturated with hexane,extracted with distilled water, concentrated in vacuo, andchromatographed over silica gel with methylene chloride/hexane (9/1) toyield the title compound as a clear, colorless oil.

¹ H NMR (DMSO) δ 7.29, 6.89, 4.08, 3.73, 3.45, 2.83, 1.85, 1.49, 1.14;¹³ C NMR (DMSO) δ 169.66, 159.19, 133.05, 126.51, 115.52, 61.66, 55.99,51.48, 34.65, 28.00, 27.01, 14.70.

Step 2 Preparation of 3-(4-methoxybenzenesulfonyl)-propylmalonic acid,diethyl ester.

A stirred mixture of 3-(4-methoxybenzenethio)-propylmalonic acid,diethyl ester (2.4 g, 7.0 mmol) in chloroform (150 mL) is cooled andm-chloroperoxybenzoic acid (3.3 g, 15 mmol) is added in small portions.After stirring overnight at ambient temperature, the mixture istransferred to chloroform/methyl alcohol (9/1) and extracted withaqueous sodium bicarbonate, brine, and concentrated in vacuo. Theconcentrate is chromatographed over silica gel using chloroform/methylalcohol (99.5/0.5), and the eluate concentrated in vacuo to yield thetitle compound as a clear, colorless oil.

¹ H NMR (DMSO) δ 7.77, 7.14, 4.06, 3.84, 3.49, 3.26, 1.79, 1.51, 1.11;¹³ C NMR (DMSO) δ 169.16, 163.67, 130.92, 115.04, 61.36, 56.23, 54.84,50.90, 27.03, 20.69, 14.32.

Step 3 Preparation of 3-(4-methoxybenzenesulfonyl)-propylmalonic acid,monoethyl ester.

To a stirred mixture of 3-(4-methoxybenzenesulfonyl)-propylmalonic acid,diethyl ester (2.0 g, 5.4 mmol) in absolute ethyl alcohol (50 mL) isadded potassium hydroxide (0.41 g, 5.9 mmol) in absolute ethyl alcohol.After stirring overnight at ambient temperature, the mixture ispartitioned between chloroform/methyl alcohol (9/1) and aqueous sodiumhydroxide. The aqueous phase is acidified with concentrated hydrochloricacid, extracted with chloroform/methyl alcohol (9/1), and the organicextracts concentrated in vacuo to yield the title compound as a clear,colorless oil.

¹ H NMR (DMSO) δ 7.18, 7.15, 4.06, 3.85, 3.36, 3.27, 1.80, 1.54, 1.13;¹³ C NMR (DMSO) δ 170.97, 169.99, 164.03, 131.32, 130.73, 61.54, 56.60,55.33, 51.57, 27.53, 21.17, 14.73.

Step 4 Preparation of 2- (4-methoxybenzenesulfonyl)propyl!-2-propenoicacid, ethyl ester.

A mixture of 3-(4-methoxybenzenesulfonyl)-propylmalonic acid, monoethylester (1.1 g, 3.2 mmol), paraformaldehyde (0.11 g, 3.5 mmol), piperidine(0.03 mL, 0.32 mmol), and pyridine (20 mL) is refluxed for three hours.The mixture is transferred to ethyl acetate and extracted with aqueous10% hydrochloric acid, distilled water, aqueous sodium bicarbonate,brine, and the organic phase is concentrated in vacuo to yield the titlecompound as a clear, colorless oil.

¹ H NMR (DMSO) δ 7.79, 7.15, 6.05, 5.59, 4.09, 3.84, 3.21, 2.29, 1.67,1.16; ¹³ C NMR (DMSO) δ 166.80, 164.05, 139.74, 131.30, 130.78, 126.72,115.44, 61.17, 56.61, 55.23, 30.45, 22.33, 14.80.

Step 5 Preparation of 2- (4-methoxybenzenethio)methyl!-5-(4methoxybenzenesulfonyl)-pentanoic acid, ethyl ester.

To a stirred mixture of 4-methoxybenzenethiol (0.30 mL, 2.2 mmol) inabsolute ethyl alcohol (1 mL) cooled in an ice bath, is added sodiumethoxide solution (0.2 mL, 0.22 mmol) followed in fifteen minutes by 2-(4-methoxybenzenesulfonyl) propyl!-2-propenoic acid, ethyl ester (0.70g, 2.2 mmol) in absolute ethyl alcohol (2 mL). After stirring overnightat ambient temperature, the mixture is transferred to ethyl acetate andextracted with aqueous 10% hydrochloric acid, distilled water, aqueoussodium bicarbonate, brine, dried over anhydrous sodium sulfate, andconcentrated in vacuo. The concentrate is triturated with hexane, thefiltered solids extracted with chloroform and concentrated in vacuo toyield the title compound as a white solid.

¹ H NMR (DMSO) δ 7.76, 7.31, 7.14, 6.86, 3.96, 3.83, 3.72, 3.16, 2.90,2.40, 1.58, 1.44, 1.08; ¹³ C NMR (DMSO) δ 173.70, 163.70, 159.18,133.49, 130.87, 125.42, 115.23, 115.04, 60.56, 56.23, 55.66, 55.00,45.05, 37.08, 29.88, 20.81, 14.48.

Step 6 Preparation of 2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanoicacid, ethyl ester.

To a stirred mixture of 2-(4-methoxybenzenethio)methyl!-5-(4-methoxybenzenesulfonyl)-pentanoicacid, ethyl ester (0.8 g, 1.8 mmol) in chloroform (50 mL) cooled in anice bath, is added m-chloroperoxybenzoic acid (0.81 g, 3.7 mmol). Afterstirring overnight at ambient temperature, the mixture is transferred toethyl acetate which is extracted with aqueous sodium bicarbonate andbrine. The organic phase is concentrated in vacuo, triturated withhexane, and the filtered solids dissolved in chloroform. The chloroformmixture is then extracted with aqueous sodium bicarbonate and brine andthe organic phase is concentrated in vacuo to yield the title compoundas a white solid.

¹ H NMR (DMSO) δ 7.75, 7.15, 3.89, 3.85, 3.50, 3.39, 3.16, 2.59, 1.57,1.42, 1.57, 1.41, 1.08; ¹³ C NMR (DMSO) δ 172.94, 164.27, 164.06,131.21, 130.95, 130.73, 115.46, 61.37, 57.29, 56.66, 56.62, 55.17,30.78, 20.81, 14.65.

Step 7 Preparation of 2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanoicacid.

A mixture of 2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanoicacid, ethyl ester (0.70 g, 1.4 mmol) in 6N hydrochloric acid (20 ml) isrefluxed overnight. The mixture is transferred to ethyl acetate which isextracted with aqueous sodium bicarbonate. The combined aqueous extractis acidified with concentrated hydrochloric acid and extracted withethyl acetate. This organic extract is concentrated in vacuo to yieldthe title compound as a white solid.

¹ H NMR (DMSO) δ 12.5, 7.77, 7.14, 3.85, 3.50, 3.32, 3.16, 2.49, 1.57,1.45; ¹³ C NMR (DMSO) δ 174.41, 164.20, 164.03, 131.29, 131.17, 130.90,130.67, 115.45, 80.03, 57.24, 56.62, 55.28, 30.68, 20.73.

Step 8 Preparation of N-benzyloxy-2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanamide.

A mixture of 2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanoicacid (0.5 g, 1.1 mmol), benzylhydroxylamine hydrochloride (0.21 g, 1.3mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.42g, 2.2 mmol), and tetrahydrofuran/water (1/1, 10 mL) is stirred atambient temperature overnight. The mixture is transferred to ethylacetate which is extracted with aqueous 10% hydrochloric acid, distilledwater, aqueous sodium bicarbonate, and brine. The organic phase isconcentrated in vacuo to yield the title compound as a white solid.

¹ H NMR (DMSO) δ 11.2, 7.76, 7.37, 7.12, 4.60, 3.84, 3.78, 3.50, 3.22,3.10, 2.39, 1.48, 1.35.

Step 9 Preparation of N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanamide.

A mixture of N-benzyloxy-2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanamide(0.3 g, 0.5 mmol), Pearlman's catalyst (0.11 g), and absolute ethylalcohol is agitated under hydrogen (15 psig) overnight at roomtemperature. The mixture is filtered and the filtrate is concentrated invacuo. The concentrate is chromatographed over silica gel withchloroform/ethyl acetate/methyl alcohol/acetic acid (50/40/10/1) and theeluate concentrated in vacuo to afford the title compound as a whitesolid.

IR (mull) 1667, 1596, 1578, 1499, 1317, 1294, 1263, 1141, 1089, 1024,837, cm⁻¹ ; MS (FAB) m/z 473, 472, 391, 371, 149, 129, 71, 57, 55, 43;Specific Rotation α!²⁵ _(D) =0; ¹ H NMR (DMSO) δ 10.5, 8.8, 7.76, 7.14,3.86, 3.42, 3.18, 2.3, 1.46.

EXAMPLE 12

Preparation ofN-hydroxy-2-(n-octylsulfonylmethyl)-3-(4-methoxybenzenesulfonyl)-propionamide.##STR14## Step 1 Preparation of 2- (n-octylthio)methyl!-2-propenoicacid.

A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol), n-octylthiol(1.2 mL, 6.6 mmol), and dimethylformamide (10 mL) is refluxed overnight.The mixture is then transferred to ethyl acetate and extracted withaqueous 10% hydrochloric acid and distilled water. The organic phase isconcentrated in vacuo to afford the title compound as a white solid.

¹ H NMR (DMSO) δ 6.00, 5.60, 3.27, 2.37, 1.46, 1.28, 1.22, 0.84; ¹³ CNMR (DMSO) δ 167.62, 138.23, 125.42, 32.28, 31.69, 31.07, 29.15, 29.06,29.02, 28.70, 22.53, 14.37.

Step 2 Preparation of 2-(n-octylthio)methyl!-3-(4-methoxybenzenethio)-propenoic acid.

A mixture of 2- (n-octylthio)methyl!-2-propenoic acid (1.0 g, 4.3 mmol),4-methoxybenzenethiol (1.1 mL, 8.6 mmol), and dimethylformamide (25 mL)is refluxed overnight. The mixture is partitioned between ethyl acetateand aqueous 10% hydrochloric acid and the organic phase is concentratedin vacuo. The concentrate is chromatographed over silica gel usingchloroform/methyl alcohol/acetic acid (98/1/1) and the eluate isconcentrated in vacuo to yield the title compound as a white solid.

¹ H NMR (DMSO) δ 12.5, 7.36, 6.90, 3.73, 3.04, 2.72, 2.55, 2.38, 1.42,1.21, 0.84; ¹³ C NMR (DMSO) δ 174.76, 159.53, 133.66, 152.92, 152.65,115.58, 55.98, 46.02, 36.80, 33.12, 32.28, 32.07, 29.87, 29.55, 29.47,29.39, 22.93, 14.75.

Step 3 Preparation of 2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)propionic acid.

To a stirred mixture of 2-(n-octylthio)methyl!-3-(4-methoxybenzenethio)-propionoic acid (0.6 g,1.6 mmol) in chloroform (15 mL) cooled in an ice bath, is addedm-chloroperoxybenzoic acid (1.4 g, 6.6 mmol). After stirring at ambienttemperature overnight, the mixture is partitioned between hexane andaqueous 10% hydrochloric acid and the aqueous phase is further extractedwith hexane and with ethyl acetate. The ethyl acetate extract isconcentrated in vacuo and chromatographed over silica gel withchloroform/methyl alcohol/acetic acid (98/1/1) to yield the titlecompound as a white solid.

¹ H NMR (DMSO) δ 7.80, 7.17, 3.68, 3.61, 3.49, 3.38, 3.02, 1.59, 1.32,1.23, 0.85.

Step 4 Preparation of N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide.

Following the general procedure outlined in EXAMPLE 4 (steps 3 and 4)and making non-critical variations but starting with 2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionic acid(0.5 g, 1.2 mmol) in step 3, the title compound is obtained as a whitesolid.

m.p. 134.5 ° C.; MS (FAB) m/z 451, 450, 434, 239, 133, 57, 43, 41, 39; ¹H NMR (DMSO) δ 10.9, 8.9, 7.80, 7.15, 3.86, 3.73, 3.50, 3.01, 2.70,2.36, 1.55, 1.08, 0.82; ¹³ C NMR (DMSO) δ 166.20, 163.90, 130.82,130.58, 115.13, 60.87, 56.27, 52.90, 52.68, 44.69, 32.98, 31.63, 28.87,28.13, 22.51, 21.63, 14.40.

EXAMPLE 13

Preparation of N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)l-propionamide.##STR15## Step 1 Preparation of 2-methyl-3-(1-methylhydantoin)!-2-propenoic acid.

A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol),1-methylhydantoin (0.85 g, 7.2 mmol), sodium bicarbonate (1.1 g, 13mmol), and toluene (50 mL) is refluxed overnight. The mixture istransferred to ethyl acetate and extracted with aqueous sodiumbicarbonate. The aqueous phase is acidified with concentratedhydrochloric acid and extracted with ethyl acetate and chloroform/methylalcohol (9/1). Concentration of the organic extracts yields the titlecompound as a solid.

¹ H NMR (DMSO) δ 6.08, 5.47, 4.08, 4.00, 2.85.

Step 2 Preparation of 2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenethio)-propionic acid.

A mixture of 2-methenyl-2- methyl-3-(1-methylhydantoin)!-propenoic acid(1.1 g, 5.5 mmol), 4-methoxybenzenethiol (0.75 mL, 6.0 mmol), sodiumbicarbonate (0.92 g, 11 mmol), and toluene (50 mL) is refluxedovernight. The mixture is concentrated in vacuo and chromatographed oversilica gel using chloroform/methyl alcohol/acetic acid (97/2/1). Theeluate is concentrated in vacuo and triturated with hexane to yield thetitle compound as a white solid.

¹ H NMR (DMSO) δ 12.3, 7.33, 6.90, 3.92, 3.74, 3.60, 2.95, 2.83, 2.74;¹³ C NMR (DMSO) δ 173.90, 171.02, 159.58, 156.98, 133.87, 152.92,115.61, 56.02, 62.01, 44.45, 40.13, 35.63, 30.01.

Step 3 Preparation of 2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionicacid.

A mixture of 2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenethio)-propionoic acid(1.0 g, 3.0 mmol) in methylene chloride (50 mL) is cooled andm-chloroperoxybenzoic acid (1.4 g, 6.3 mmol) is added. After stirring atambient temperature overnight, the mixture is concentrated in vacuo andchromatographed over silica gel 60 (230-400 mesh) usingchloroform/methyl alcohol/acetic acid (94/5/1). The eluate isconcentrated in vacuo to yield the title compound as a white solid.

¹ H NMR (DMSO) δ 7.75, 7.14, 3.87, 3.84, 3.54, 3.35, 2.92, 2.80.

Step 4 Preparation of N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.

Following the general procedure outlined in EXAMPLE 4 (steps 3 and 4)and making non-critical variations but starting with 2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionoicacid (0.6 g, 1.6 mmol) in step 3 the title compound is obtained.

MS (EI) m/z 385 (M+), 214, 181, 172, 171, 155, 123, 107, 99, 77, 56; ¹ HNMR (DMSO) δ 10.8, 8.2, 7.76, 7.13, 3.84, 3.44, 3.24, 2.81; ¹³ C NMR(DMSO) δ 170.68, 166.39, 163.77, 156.41, 130.72, 130.51, 115.06, 56.26,54.99, 51.68, 39.68, 37.24, 29.66.

EXAMPLE 14

Preparation of N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide.##STR16## Step 1 Preparation of 4-butoxybenzenesulfinic acid, sodiumsalt.

To a stirred mixture of sodium iodide (8.8 g, 59 mmol) in acetone (250mL) is added 4-butoxybenzenesulfonyl chloride (5.0 g, 20 mmol). Afterstirring at ambient temperature overnight, the mixture is filtered andthe filtered solids washed with acetone to afford4-butoxybenzenesulfinic acid, sodium salt as a white solid.

¹ H NMR (DMSO) δ 7.49, 6.81, 3.93, 1.67, 1.40, 0.90.

Step 2 Preparation of 2- (4-butoxybenzenesulfonyl)methyl!-2-propenoicacid.

A mixture of 2-bromomethylacrylic acid (1.0 g, 6.0 mmol),4-butoxybenzenesulfinic acid, sodium salt (3.1 g, 13 mmol), sodiumcarbonate (1.9 g, 18 mmol) and dimethylformamide (20 mL) is refluxedovernight. The reaction mixture is then partitioned between ethylacetate and aqueous 10% hydrochloric acid and the organic phase isconcentrated in vacuo. The concentrate is chromatographed over silicagel 60 (230-400 mesh) with chloroform/methyl alcohol/acetic acid(94/5/1) and the eluate concentrated in vacuo to afford the titlecompound as a white solid.

¹ H NMR (DMSO) δ 12.9, 7.67, 7.10, 6.28, 5.70, 4.22, 4.03, 1.68, 1.41,0.90; ¹³ C NMR (DMSO) δ 167.04, 163.63, 133.06, 131.33, 130.91, 130.47,114.08, 68.69, 57.60, 31.33, 19.48, 14.47.

Step 3 Preparation of 2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionoicacid.

A mixture of 2- (4-butoxybenzenesulfonyl)methyl!-2-propenoic acid (1.0g, 3.4 mmol), 1-butylhydantoin (0.78 g, 5.0 mmol), sodium bicarbonate(0.63 g, 7.4 mmol), and toluene (50 mL) is refluxed overnight. Thereaction mixture is transferred to ethyl acetate, extracted with aqueous10% hydrochloric acid, and concentrated in vacuo. The concentrate istriturated with hexane and diethyl ether to yield the title compound asa white solid.

¹ H NMR (DMSO) δ 7.73, 7.14, 5.74, 4.07, 3.90, 3.59, 3.54, 3.23, 2.95,1.72, 1.42, 1.24, 0.93, 0.87; ¹³ C NMR (DMSO) δ 172.46, 171.21, 163.73,156.53, 130.89, 130.63, 115.88, 68.73, 55.72, 55.52, 49.94, 42.42,31.32, 29.83, 20.02, 19.47, 14.47, 14.34.

Step 4 Preparation of N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide.

Following the general procedure outlined in EXAMPLE 4 (steps 3 and 4)and making non-critical variations but starting with 2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionoic acid(0.59 g, 1.3 mmol) in step 3 the title compound is obtained as a whitesolid.

MS (FAB) m/z 471, 470, 469, 223, 197, 149, 57, 41, 23; ¹ H NMR (DMSO) δ10.8, 8.8, 7.74, 7.10, 5.73, 4.06, 3.88, 3.47, 3.21, 2.82, 1.71, 1.42,1.25, 0.92, 0.87.

EXAMPLE 15

Preparation of N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.##STR17##

Following the general procedure outlined in EXAMPLE 14 (steps 1 to 4)and making non-critical variations but starting with4-methoxybenzenesulfonyl chloride in step 1, the title compound isobtained as a white solid.

MS (FAB) m/z 428 (MH+), 429, 428, 223, 149, 129, 71, 57, 55, 43, 41; ¹ HNMR (DMSO) δ 10.80, 8.81, 7.77, 7.12, 3.85, 3.49, 3.23, 2.83, 1.43,1.24, 0.88; ¹³ C NMR (DMSO) δ 170.79, 166.40, 163.77, 156.17, 130.78,130.47, 115.08, 55.26, 55.08, 46.63, 42.10, 41.2, 37.25, 29.49, 19.68,13.99.

EXAMPLE 16

Preparation of N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.##STR18##

Following the general procedure outlined in EXAMPLE 14 (steps 1 to 4)and making non-critical variations but starting with5,5-dimethylhydantoin (1.5 g, 11 mmol) in step 3, the title compound isobtained as a white solid.

¹ H NMR (DMSO) δ 10.8, 8.2, 7.77, 7.12, 3.84, 3.41, 3.17, 2.85, 1.21; ¹³C NMR (DMSO) δ 177.62, 166.35, 163.82, 155.28, 130.85, 130.49, 115.14,58.16, 56.26, 55.37, 37.20, 24.95, 24.87.

EXAMPLE 17

Preparation of (+)-N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide and(-)-N-hydroxy-2- (n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)propionamide.

A racemic mixture of N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-3-(n-octylsulfonyl)propionamide(EXAMPLE 12) is eluted over a Chiralpak AD, column with absolute ethylalcohol and the eluates collected at R_(f) =13.5 minutes and R_(f) =23.5minutes are concentrated in vacuo to yield an enantiomer (17A) ( α!²⁵_(D) =+4°) and an enantiomer (17B) ( α!²⁵ _(D) =-4°), respectively.

EXAMPLE 18

Preparation of (+)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamideand (-)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.

A racemic mixture of N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide(EXAMPLE 13) is eluted over a Chiralpak AD, column with absolute ethylalcohol and the eluates collected at R_(f) =8.6 minutes and R_(f) =10.5minutes are concentrated in vacuo to yield the enantiomers, 18A and 18B,respectively.

EXAMPLE 19

Preparation of (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamideand (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide.

A racemic mixture of N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide(EXAMPLE 14) is eluted over a Chiralpak AD column with absolute ethylalcohol and the eluates collected at R_(f) =16.5 minutes and R_(f) =17.8minutes are concentrated in vacuo to yield an enantiomer (19A) ( α!²⁵_(D) =-3°) and an enantiomer (19B) ( α!²⁵ _(D) =+3°), respectively.

EXAMPLE 20

Preparation of (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamideand (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.

A racemic mixture of N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide(EXAMPLE 15) is eluted over a Chiralpak AD column with absolute ethylalcohol and the eluates collected at R_(f) =13.4 minutes and R_(f) =15.8minutes are concentrated in vacuo to yield an enantiomer (20A) ( α!²⁵_(D) =-4°) and an enantiomer (20B) ( α!²⁵ _(D) =+4°), respectively.

EXAMPLE 21

Biological Activity Test

Inhibitory activity is evaluated in one or more of the MMP enzymes(stromelysin, gelatinase, and collagenase) in vitro using particleconcentration fluorescence assay. An inhibitor binds to MMP enzymeswhich prevents the degradation of a substrate by stromelysin,gelatinase, or collagenase. The substrate has attached to it afluorescein and a biotin moiety. The intact substrate then binds to anavidin-coated particle via the biotin moiety. Once the particle iswashed and dried, a fluorescent signal is generated since thefluorescent group is attached to the particle. Without an inhibitorpresent, the substrate is degraded by MMP enzymes and the fluoresceingroup is removed, therefore, no fluorescent signal can be detected.Testing compounds are dissolved in DMSO to the desired concentration,then the solutions are diluted to 1:5 with MMP buffer (50 mM Tris-HCl,pH 7.5; 150 mM NaCl; 0.02% NaN₃). Serial two-fold dilutions of eachcompound are prepared. A concentrated, activated enzyme solution istransferred into each plate of the testing compounds, and the mixture isincubated at room temperature for 15 minutes. Thawed MMP substrate isthen added into all plates, and the plates are incubated in the dark for1-3 hours at room temperature. At this point, the substrate mixture ismixed with 0.1% avidin-coated polystyrene particles. After 15 minutes,the fluorescence values are measured following filtration and washing ofthe beads. Ki values are then calculated. Inhibitory data for thecompounds of this invention are shown in TABLE 1. Compounds with lowerKi values are expected to be more effective as MMP inhibitors. It isexpected that a compound with a Ki less than 15 μM against stromelysinwill display therapeutic effects in connective tissue disorders.

                  TABLE 1                                                         ______________________________________                                        MMP Inhibition Constants (Ki, μM) of the Compounds of the Invention                       Stromelysin                                                                             Gelatinase                                           Example No.    Ki (μM)                                                                              Ki (μM)                                           ______________________________________                                        1              0.049     0.0092                                               2              1.1       0.087                                                3              3.6       0.081                                                4              0.0039    0.00019                                              5              0.072     0.0019                                               6              0.092     0.0025                                               7              1         0.35                                                 8              0.44      0.19                                                 9              0.13      0.0038                                               10             0.16      0.008                                                11             0.001     0.001                                                12             0.0054    0.00082                                              13             0.017     0.0013                                               14             0.0018    0.000092                                             15             0.009     0.00034                                              ______________________________________                                         ##STR19##                                                                 

We claim:
 1. A compound of formula Ior pharmaceutical acceptable saltsthereof wherein: R₁ isa) C₄₋₁₂ alkyl, b) C₄₋₁₂ alkenyl, c) C₄₋₁₂alkynyl, d) --(CH₂)_(h) -C₃₋₈ cycloalkyl, e) --(CH₂)_(h) -aryl, f)--(CH₂)_(h) -aryl substituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, halo, --NO₂,--CF₃, --CN, or --N(C₁₋₄ alkyl)₂, g) --(CH₂)_(h) -het, or h) --(CH₂)_(h)-het substituted with C₁₋₄ alkyl, or halo; R₂ isa) C₁₋₁₂ alkyl, b) C₁₋₁₂alkyl substituted with one to three halo, --CN, --NO₂, --CF₃, --N(R₃)₂,--SR₃, or OH, c) C₂₋₁₂ alkenyl, d) C₂₋₁₂ alkenyl substituted with one tothree halo, --CN, --NO₂, or --CF₃, e) C₂₋₁₂ alkynyl, f) C₂₋₁₂ alkynylsubstituted with one to three halo, --CN, --NO₂, or --CF₃, g)--(CH₂)_(h) -C₃₋₈ cycloalkyl, h) --(CH₂)_(h) -C₃₋₈ cycloalkylsubstituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy, or halo, i)--(CH₂)_(h) -C₃₋₈ cycloalkenyl, j) --(CH₂)_(h) -C₃₋₈ cycloalkenylsubstituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy, or halo, k)--(CH₂)_(h) -aryl, l) --(CH₂)_(h) -aryl substituted with one to threeC₁₋₄ alkyl, C₁₋₄ alkoxy, --CF₃ --OH, --NO₂, --CN, --N(R₃)₂, --SR₃, --SO₂(C₁₋₄ alkoxy), --C(═O)R₃, or --NC(═O)R₃, m) --(CH₂)_(h) -arylsubstituted with one to five halo, n) --(CH₂)_(h) -het, o) --(CH₂)_(h)-het substituted with one to two C₁₋₄ alkyl, or halo, p) --(CH₂)_(h) -Q,q) --(CH₂)_(h) -Q substituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy,halo, or phenyl, r) --(CH₂)_(i) -X-R₄, optionally the --(CH₂)_(i) -chain can be substituted with C₁₋₄ alkyl or phenyl, which in turn can besubstituted with one to three halo or C₁₋₄ alkyl, or s) --(CH₂)_(i) CHR₅R₆ ; R₃ isa) H, b) C₁₋₄ alkyl, c) --(CH₂)_(h) -phenyl, or d) --(CH₂)_(h)-phenyl substituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy, or halo;X isa) --O--, b) --S(═O)_(j) -, c) --NR₇ -, d) --S(═O)₂ NR₈ -, or e)--C(═O)--; R₄ isa) H, b) C₁₋₄ alkyl, c) --(CH₂)_(h) -phenyl, d)--(CH₂)_(h) -phenyl substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy, halo, --NO₂, or --CN, or e) --(CH₂)_(h) -het; R₅ isa) C₁₋₄alkyl, or b) --C(═O)R₃ ; R₆ isa) --C(═O)R₃, or b) --(CH₂)_(h) C(═O)R₃ ;R₇ isa) H, b) C₁₋₄ alkyl, c) --(CH₂)_(h) -phenyl, d) --(CH₂)_(h) -phenylsubstituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy, or halo, e)--C(═O)--R₃, f) --S(═O)₂ R₃, or g) --C(═O)OR₃ ; R₈ is a) C₁₋₄ alkyl, b)--(CH₂)_(h) -phenyl, or c) --(CH₂)_(h) -phenyl substituted with one tothree C₁₋₄ alkyl, C₁₋₄ alkoxy, or halo; aryl is monocarbocyclic, orbicarbocyclic aromatic moiety; het is 5- to 10-membered unsaturatedheterocyclic moiety having one to three atoms selected from the groupconsisting of oxygen, nitrogen, and sulfur; Q is 5- to 10-memberedsaturated heterocyclic moiety having one to two atoms selected from thegroup consisting of oxygen, nitrogen, and sulfur; h is 0, 1, 2, 3, 4, 5,or 6; i is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and j is 0, 1, or
 2. 2.A compound of formula I according to claim 1 whereinR₂ isa) C₁₋₁₂ alkylsubstituted with one to three halo, --CN, --NO₂, --CF₃, --N(R₃)₂, --SR₃,or OH, b) C₂₋₁₂ alkenyl, c) C₂₋₁₂ alkenyl substituted with one to threehalo, --CN, --NO₂, or --CF₃, d) C₂₋₁₂ alkynyl, e) C₂₋₁₂ alkynylsubstituted with one to three halo, --CN, --NO₂, or --CF₃, f)--(CH₂)_(h) -C₃₋₈ cycloalkyl substituted with one to three C₁₋₄ alkyl,C₁₋₄ alkoxy, or halo, g) --(CH₂)_(h) -C₃₋₈ cycloalkenyl, h) --(CH₂)_(h)-C₃₋₈ cycloalkenyl substituted with one to three C₁₋₄ alkyl, C₁₋₄alkoxy, or halo, i) aryl, j) aryl substituted with one to three C₁₋₄alkyl, C₁₋₄ alkoxy, --CF₃ --OH, --NO₂, --CN, --N(R₃)₂, --SR₃,--SO₂ (C₁₋₄alkoxy), --C(═O)R₃, or --NC(═O)R₃, k) --(CH₂)_(h) -het, l) --(CH₂)_(h)-het substituted with one to two C₁₋₄ alkyl, or halo, m) --(CH₂)_(i) -Q,n) --(CH₂)_(i) -Q substituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy,halo, or phenyl, o) --(CH₂)_(i) -X-R₄, optionally the --(CH₂)_(i) -chain can be substituted with C₁₋₄ alkyl or phenyl, which in turn can besubstituted with one to three halo or C₁₋₄ alkyl, or p) --(CH₂)_(h) CHR₅R₆ ; wherein R₃, X, R₄, R₅, R₆, R₇, R₈, aryl, het and Q are as definedas in claim 1; h is 0, 1, 2, 3, 4, 5, or 6; and i is 1, 2, 3, 4, 5 or 6.3. A compound of formula I according to claim 1 whereinR₂ isa)--(CH₂)_(h) -het, b) --(CH₂)_(h) -het substituted with one to two C₁₋₄alkyl, or halo, c) --(CH₂)_(i) -Q, d) --(CH₂)_(i) -Q substituted withone to three C₁₋₄ alkyl, C₁₋₄ alkoxy, halo, or phenyl, or e) --(CH₂)_(i)-X-R₄, optionally the --(CH₂)_(i) - chain can be substituted with C₁₋₄alkyl or phenyl, which in turn can be substituted with one to three haloor C₁₋₄ alkyl; wherein X, R₄, R₇, R₈, aryl, het and Q are as defined asin claim 1; h is 0, 1, 2, 3, 4, 5, or 6; and i is 1, 2, 3, 4, 5 or
 6. 4.A compound of formula I according to claim 1 whereinR₁ isa) C₄₋₈ alkyl,b) --(CH₂)_(h) -phenyl, or c) --(CH₂)_(h) -phenyl substituted with C₁₋₄alkyl, C₁₋₄ alkoxy, fluoro, chloro, or bromo; R₂ isa) --(CH₂)_(h)-pyridyl, quinolinyl, pyrrolyl, thienyl, or thiazolyl, or indolyl, whichcan optionally be substituted with one to three C₁₋₄ alkyl, C₁₋₄ alkoxy,phenyl, fluoro, chloro, or bromo; b) --(CH₂)_(h) -piperdinyl,piperazinyl, morpholino, 4-thiomorpholinyl, butyrolactamyl,2-oxo-oxazolidinyl, or 2,4-dioxo-imidazolidinyl, which can optionally besubstituted with one to three C₁₋₄ alkyl, phenyl, fluoro, chloro, orbromo; c) --(CH₂)_(i) -X-R₄ ; X isa) --S(═O)_(j) --, R₄ isa) C₁₋₈ alkyl,b) phenyl, or c) phenyl substituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, orhalo; h is 0, 1, 2, 3, 4, 5 or 6; i is 1, 2, 3, 4, 5 or 6; and j is 0, 1or
 2. 5. A compound of claim 1 wherein R₁ is selected from the groupconsisting of n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl,3-methybutyl, n-hexyl, n-heptyl, n-octyl, phenyl, 4-methylphenyl,4-ethylphenyl, 4-tert-butylphenyl, 4-chlorophenyl, 4-isopropylphenyl,4-bromophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-n-butoxyphenyl, benzyl, 4-phenylbenzyl, 2-, 3-, or4-fluorobenzyl, 2-, 3-, 4-chlorobenzyl, 2-, 3-, 4-bromobenzyl, and4-ethoxybenzyl.
 6. A compound of claim 1 wherein R₁ is selected from thegroup consisting of n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,phenyl, 4-methylphenyl, 4-ethylphenyl, 4-chlorophenyl, 4-bromophenyl,4-fluorophenyl, 4-methoxyphenyl, 4-n-butoxyphenyl, benzyl,4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, and 4-ethoxybenzyl.
 7. Acompound of claim 1 wherein R₂ is selected from the group consisting ofmethyl, 1-cyano-1-phenyl methyl, 2-cyano ethyl, 2-phenylethyl,2-bromo-2-phenylethyl, 2-bromoethyl, propyl, isopropyl, 3-chloropropyl,3-bromopropyl, n-butyl, isobutyl, 3-methylbutyl, 1-methylpropyl,tert-butyl, n-pentyl, 3-methybutyl, n-hexyl, n-heptyl, n-octyl,n-hexadecyl, n-octadecyl, 2-propenyl, 2-propynyl, 3-butenyl, 4-pentenyl,3-butenynyl, 4-pentenynyl, cyclopentyl, cyclohexyl, cyclohexylmethyl,2-cyclohexylethyl, 4-cyclohexylbutyl, dimethylaminoethyl,dimethylaminopropyl, diethylaminopropyl, phenylaminomethyl, phenyl,4-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-fluorophenyl,4-trifluoromethylphenyl, 2-methoxyphenyl, 4-methoxyphenyl,4-nitrophenyl, 4-ethoxyphenyl, benzyl, 4-methylbenzyl, 2-fluorobenzyl,3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl,4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, and2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-ethoxybenzyl,4-nitrobenzyl, methylcarbonyl, 1-methylcarbonyl methyl, 2-phenylcarbonylethyl, isopropylcarbonyl, methoxycarbonyl, ethoxycarbonyl,1,1-ethoxycarbonyl methyl, 2,2-ethoxycarbonyl ethyl, 1,2-ethoxycarbonylethyl, 2-methoxycarbonyl propyl, 3-methoxycarbonyl propyl,1-ethoxycarbonyl methyl, 1-ethoxycarbonyl ethyl, phenylcarbonyl,phenylcarbonyl methyl, pyridylcarbonyl methyl, pyridylmethyl,pyridylethyl, quinolinylmethyl, pyrrolyl methyl, indolyl methyl,thienyl, thiazolyl, thienylmethyl, thienylethyl, piperdinyl methyl,piperazinyl methyl, morpholino methyl, morpholino ethyl, morpholinopropyl, thiomorpholino methyl, thiomorpholino propyl,4-methoxybenzenesulfonyl methyl, 3-(4-methoxybenzenesulfonyl)aminopropyl, 3-hydroxy, amino, 3-phenoxy propyl, 2-phenyl ethyloxy,(4-butoxybenzenesulfonyl)methyl, methyl-3-(1,5,5-trimethylhydantoin),methyl-3-(1-butyl-5,5-dimethylhydantoin),(4-methoxybenzenesulfonyl)methyl, (4-chlorobenzenesulfonyl)-methyl,(4-bromobenzenesulfonyl)methyl, (n-butylsulfonyl)methyl,(n-octylsulfonyl)-methyl, 3-(4-methoxybenzenesulfonyl)propyl,(4-methylbenzenesulfonyl)methyl, (benzenesulfonyl)methyl,methyl-3-(1-methylhydantoin), methyl-3-(1-butylhydantoin) andmethyl-3-(5,5-dimethylhydantoin).
 8. A compound of claim 1 wherein R₂ isselected from the group consisting of (4-methoxybenzenesulfonyl)methyl,(4-chlorobenzenesulfonyl)-methyl, (4-bromobenzenesulfonyl)methyl,(n-butylsulfonyl)methyl, (n-octylsulfonyl)-methyl,3-(4-methoxybenzenesulfonyl)propyl, (4-methylbenzenesulfonyl)methyl,(benzenesulfonyl)methyl, methyl-3-(1-methylhydantoin), methyl-3-(1-butylhydantoin) and methyl-3-(5,5-dimethylhydantoin).
 9. A compound ofclaim 1 which is(1) N-hydroxy 2- (4-methoxybenzenesulfonyl)methyl!-3-phenyl-propionamide, (2) N-hydroxy 2-(benzenesulfonyl)methyl!-3-phenyl-propionamide, (3) N-hydroxy 2-(benzenesulfonyl)methyl!-propionamide, (4) N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide,(5) N-hydroxy-2-(4-chlorobenzenesulfonyl)methyl!-3-(4-chlorobenzenesulfonyl)-propionamide,(6) N-hydroxy-2-(4-bromobenzenesulfonyl)methyl!-3-(4-bromobenzenesulfonyl)-propionamide,(7) N-hydroxy-2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionamide, (8)N-hydroxy-2- (n-octylsulfonyl)methyl!-3-(n-octylsulfonyl)-propionamide,(9) N-hydroxy-2-(4-methylbenzenesulfonyl)methyl!-3-(4-methylbenzenesulfonyl)-propionamide,(10) N-hydroxy-2-(benzenesulfonyl)methyl!-3-(benzenesulfonyl)-propionamide, (11)N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanamide,(12) N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide, (13)N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(14) N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,(15) N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(16) N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzene-sulfonyl)-propionamide,(17) (+)-N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide, (18)(-)-N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide, (19)(+)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(20) (-)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(21) (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,(22) (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,(23) (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(24) (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(25) (+)-N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,or (26) (-)-N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.10. A compound of claim 1 which is(1) N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide,(2) N-hydroxy-2-(4-chlorobenzenesulfonyl)methyl!-3-(4-chlorobenzenesulfonyl)-propionamide,(3) N-hydroxy-2-(4-bromobenzenesulfonyl)methyl!-3-(4-bromobenzenesulfonyl)-propionamide,(4) N-hydroxy-2-(n-butylsulfonyl)methyl!-3-(n-butylsulfonyl)-propionamide, (5)N-hydroxy-2- (n-octylsulfonyl)methyl!-3-(n-octylsulfonyl)-propionamide,(6) N-hydroxy-2-(4-methylbenzenesulfonyl)methyl!-3-(4-methylbenzenesulfonyl)-propionamide,(7) N-hydroxy-2-(benzenesulfonyl)methyl!-3-(benzenesulfonyl)-propionamide (8)N-hydroxy-2-(4-methoxybenzenesulfonyl)methyl!-5-(4-methoxybenzenesulfonyl)-pentanamide,(9) N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide, (10)N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(11) N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,(12) N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(13) N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(14) (+)-N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide, (15)(-)-N-hydroxy-2-(n-octylsulfonyl)methyl!-3-(4-methoxybenzenesulfonyl)-propionamide, (16)(+)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(17) (-)-N-hydroxy-2-methyl-3-(1-methylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(18) (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,(19) (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-butoxybenzenesulfonyl)-propionamide,(20) (+)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(21) (-)-N-hydroxy-2-methyl-3-(1-butylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,(22) (+)-N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide,or (23) (-)-N-hydroxy-2-methyl-3-(5,5-dimethylhydantoin)!-3-(4-methoxybenzenesulfonyl)-propionamide.11. A method of inhibiting excess matrix metalloproteinase whichcomprises administering to a patient in need thereof an effective amountof a compound of claim
 1. 12. The method of claim 11 wherein matrixmetalloproteinases comprises stromelysin, collagenase, and gelatinase.13. A method of treating a human suffering from or susceptible todiseases involving connective tissue degradation which comprisesadministering to a patient in need thereof an effective amount of acompound of claim
 1. 14. The method of claim 13 wherein the diseasesrelated to connective tissue degradation are osteoarthrits, rheumatoidarthritis, septic arthritis, osteopenias, steoporosis, tumor metastasis,periodontitis, gingivitis, corneal epidermal ulceration, or gastriculceration.
 15. The method of claim 11 wherein the effective amount ofthe compound of claim 1 is administered orally, parenterally, ortopically in a pharmaceutical composition.
 16. The method of claim 13wherein the effective amount of the compound of claim 1 is administeredorally, parenterally, or topically in a pharmaceutical composition. 17.The method of claim 11 or 13 wherein said compound is administered in anamount of from about 0.1 to about 100 mg/kg of body weight/day.
 18. Apharmaceutical composition which comprises an amount of the compound ofclaim 1 effective to inhibit excess matrix metalloproteinase and apharmaceutically acceptable carrier.